This application is directed to new types of hydroxamic acid-based bifunctional chelators. These chelators preferably chelate metal ions that can be detected either by their paramagnetic or radioactive properties.
Natural substances containing hydroxamic acid functionalities in their structures exhibit a wide variety of biological activities. Frequently, they act in vivo as antibiotics, growth factors, and iron-transport agents. Siderophores represent one type of natural substance that contain hydroxamic acid functionalities. Siderophores are small iron-chelating molecules produced by the organism when iron deficiencies occur. There are mainly two classes of siderophores, the cathecolamides and the hydroxamates. The cathecolamide class includes, for example, parabactin and vibriobactin. The hydroxamate class includes, for example, bisucaberin (macro-cyclic), desferrioxamine B (linear), desferrioxamine G (linear) and desferrioxamine E (macrocyclic). Because of their numerous potential applications, such as in the treatment of iron overload, also known as Cooley""s anemia, as contrast agents for NMR imaging, and as diagnostic and therapeutic radiopharmaceuticals, the design and synthesis of new chelators possessing hydroxamic acid residues have attracted the attention of several research groups.
It is one object of this invention to provide chelators that can be attached to peptides and proteins by forming a thiourea or amide bond.
It is a further object of this invention to provide compounds that include diagnostic and therapeutic agents.
It is yet another object of this invention to provide improvements in research and diagnostic methods and materials for assaying bodily states in animals, especially disease states.
These and other objects are satisfied by the present inventions, which in one aspect provide chelators that can be attached to peptides or proteins. The chelators of the invention generally possess hydroxamic acid functionalities and can be bound to peptides and/or proteins, by forming a thiourea or amide bond. Preferred chelators have any of the formulas I, II, or III: 
where n, m and o are, independently, an integer from 1 to about 4;
X is CH2, nitrogen (N(R4)), oxygen or sulfur;
Y is hydrogen, xe2x80x94OH (hydroxyl),xe2x95x90O (carbonyl), N(R4)(R5), or xe2x95x90S;
R1 is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group;
R2 is an active group such as an activated ester, a carboxylic acid, an alkyl isothiocyanate, an aromatic isothiocyanate or a leaving group (such as I, Br, Cl, F, mesylate, tosylate, trifluorosulfonate (triflate);
R3 is hydrogen or a protective group;
R4 is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group;
R5 is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group;
Z1 is hydrogen, nitrogen, oxygen, or sulfur;
Z2 is hydrogen, nitrogen, oxygen, or sulfur;
In preferred embodiments, the activated ester is one of the following: 
The carboxylic acid group can be preferably: 
The isothiocyanato group preferably is one of the following: 
and the protective group preferably is: 
In another aspect, the present inventions also provide methods for diagnosis and treatment of receptor-positive tumors. Once linked to biologically active ligands, the conjugates can be complexed to a radioisotope metallic element and used for diagnosing or treating any appropriate receptor-positive tumors.